Tamoxifen (TAM) is an adjuvant therapy for women with estrogen receptor (ER) (+) breast cancer, acting as an estrogen antagonist. Women taking TAM report the use of complementary dietary supplements including phytoestrogen-rich foods such as soy and flaxseed to reduce tumor growth and recurrence and TAM-induced menopausal symptoms. However, the interactive effects of TAM and flaxseed on ER(+) breast cancer has not been tested in animal or human models. Therefore the long term objective of this study is to determine whether flaxseed can enhance the tumor inhibitory effect of TAM in both premenopausal and postmenopausal women. The specific aims are: (1) to determine the effect of flaxseed and TAM, alone and in combination, on the growth of human ER(+) breast cancer (i.e. MCF-7), in the presence of high or low concentrations of estrogen and (2) to determine some of the mechanisms. The study plan is to inject ovariectomized athymic mice with MCF-7 cells, implant them with a pellet containing 1.7 mg estradiol (E2), and then feed them with basal diet (BD). In Experiment 1, at week 5 when the tumors are already established, the E2 pellet will be removed and replaced by a new one (to simulate high E2 levels in premenopausal women). The mice will then be randomized into 7 groups such that they have similar mean tumor size: Groups 1, 4 and 7 will be fed the BD, Groups 2 and 5, the 5 % flaxseed, groups 3 and 6, the 10% flaxseed. Groups 4, 5 and 6 will also receive an implant of TAM (5 mg) pellet. Group 7 will not have E2 replaced (negative control). In Experiment 2, the plan is the same as in Experiment 1 except that at week 5, the existing E2 pellet will be removed from all mice (to simulate low E2 levels in postmenopausal women) before randomization to 7 groups. Group 7 will have the E2 replaced (positive control). In both experiments, palpable tumors will be measured weekly and at week 20, will be excised for analysis to explore potential mechanisms, including cell proliferation, apoptosis, angiogenesis, expression of ER and growth factors.